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<p>Although multiple cellular pathways have been implicated in α-Synuclein (α-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. In this study, we identify <i>Drosophila mino</i>, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of α-syn. Silencing the expression of <i>mino</i> significantly suppresses α-syn-induced PD phenotypes in <i>Drosophila</i>, including dopaminergic neuronal loss and locomotion defects as well as circadian rhythm-related activities, whereas <i>mino</i> overexpression yields opposite effects. Mechanistically, we find that <i>mino</i> modulates the levels of mitochondrial reactive oxygen species and lipid peroxidation. Importantly, treatment of α-syn-expressing flies with FSG67, a GPAT inhibitor of glycerol 3-phosphate acyltransferase, reproduces the benefits of <i>mino</i> knockdown. FSG67 also inhibits α-syn aggregation and lipid peroxidation in mouse primary neurons treated with α-syn preformed fibrils. Our study elucidates an important factor contributing to α-syn toxicity and offers a therapeutic direction for PD.</p>

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Glycerol 3-phosphate acyltransferase exacerbates α-synuclein-induced toxicity by increasing lipid peroxidation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Mengda Ren,
  • Grace G. Y. Lim,
  • Willcyn Tang,
  • Kah-Leong Lim

摘要

Although multiple cellular pathways have been implicated in α-Synuclein (α-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. In this study, we identify Drosophila mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of α-syn. Silencing the expression of mino significantly suppresses α-syn-induced PD phenotypes in Drosophila, including dopaminergic neuronal loss and locomotion defects as well as circadian rhythm-related activities, whereas mino overexpression yields opposite effects. Mechanistically, we find that mino modulates the levels of mitochondrial reactive oxygen species and lipid peroxidation. Importantly, treatment of α-syn-expressing flies with FSG67, a GPAT inhibitor of glycerol 3-phosphate acyltransferase, reproduces the benefits of mino knockdown. FSG67 also inhibits α-syn aggregation and lipid peroxidation in mouse primary neurons treated with α-syn preformed fibrils. Our study elucidates an important factor contributing to α-syn toxicity and offers a therapeutic direction for PD.